Stimulation of Oxytocin Receptor during Early Reperfusion Period Protects the Heart against Ischemia/Reperfusion Injury: the Role of Mitochondrial ATPSensitive Potassium Channel, Nitric Oxide, and Prostaglandins
Postconditioning is a simple and safe strategy for cardioprotection and infarct size limitation. Our previous study showed that oxytocin (OT) exerts postconditioning effect on ischemic/reperfused isolated rat heart. The aim of this study was to investigate the involvement of OT receptor, mitochondrial ATP-sensitive potassium channel (mKATP), nitric oxide (NO) and cyclooxygenase (COX) pathways in OT postconditioning. Isolated rat hearts were divided into10 groups and underwent 30 min of regional ischemia followed by 120 min of reperfusion (n =6). In I/R (ischemia/reperfusion) group, ischemia and reperfusion were induced without any treatment. In OT group, oxytocin was perfused 5 min prior to beginning of reperfusion for 25 min. In groups 3-6, atosiban (oxytocin receptor blocker), L-NAME (N-Nitro-L-Arginine Methyl Ester, non-specific nitric oxide synthase inhibitor), 5-HD (5-hydroxydecanoate, mKATP inhibitor) and indomethacin (cyclooxygenase inhibitor) were infused prior to oxytocin administration. In others, he mentioned inhibitors were perfused prior to ischemia without oxytocin infusion. Infarct size, ventricular hemodynamic, coronary effluent, malondialdehyde (MDA) and lactate dehydrogenase (LDH) were measured at the end of reperfusion. OT perfusion significantly reduced infarct size, MDA and LDH in comparison with IR group. Atosiban, 5HD, L-NAME and indomethacin abolished the postconditioning effect of OT. Perfusion of the inhibitors alone prior to ischemia had no effect on infarct size, hemodynamic parameters, coronaryeffluent and biochemical markers as compared with I/R group. In conclusion, this study indicates that postconditioning effects of OT are mediated by activation of mKATP and production of NO and Prostaglandins (PGs).
Heusch G, Musiolik J, Gedik N, et al. Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 2011;109(11):1302-8.
Wei M, Xin P, Li S, et al. Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circ Res 2011;108(10):1220-25.
3. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003; 285(2):H579-88.
Tian Y, Zhang W, Xia D, et al. Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway. J Biomed Sci 2011;18(1):53.
Penna C, Cappello S, Mancardi D, et al. Post-conditioning reduces infarct size in the isolated rat heart: role of coronary flow and pressure and the nitric oxide/cGMP pathway. Basic Res Cardiol 2006;101(2):168-79.
Yang XM, Proctor JB, Cui L, et al. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol 2004; 44(5):1103-110.
Rastaldo R, Pagliaro P, Cappello S, et al. Nitric oxide and cardiac function. Life Sci 2007;81(10):779-93.
Faghihi M, Alizadeh AM, Khori V, et al. The role of nitric oxide, reactive oxygen species, and protein kinase C in oxytocin-induced cardioprotection in ischemic rat heart. Peptides 2012;37(2):314-19.
Hausenloy DJ. Signalling pathways in ischaemic postconditioning. Thromb Haemost 2009;101(4):626-34.
Argaud L, Gateau-Roesch O, Raisky O, et al. Postconditioning inhibits mitochondrial permeability transition. Circulation 2005; 111(2):194-7.
Serviddio G, Di Venosa N, Federici A, et al. Brief hypoxia before normoxic reperfusion (postconditioning) protects the heart against ischemia-reperfusion injury by preventing mitochondria peroxyde production and glutathione depletion. FASEB J 2005; 19(3):354-61.
Vinten-Johansen J, Zhao ZQ, Zatta AJ, et al. Postconditioning--A new link in nature's armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol 2005;100(4):295-310.
Schipke JD, Kerendi F, Gams E, et al. Postconditioning: a brief review. Herz 2006; 31(6):600-6.
Penna C, Mancardi D, Rastaldo R, et al. Cardioprotection: a radical view Free radicals in pre and postconditioning. Biochim Biophys Acta 2009;1787(7):781-93.
Birnbaum Y, Ye Y, Rosanio S, et al. Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury. Cardiovasc Res 2005;65(2):345-55.
Bassuk JA, Wu D, Lozano H, et al. Non-selective cyclooxygenase inhibition before periodic acceleration (pGz) cardiopulmonary resuscitation (CPR) in a porcine model of ventricular fibrillation. Resuscitation 2008;77(2):250-7.
Camitta MG, Gabel SA, Chulada P, et al. Cyclooxygenase- 1 and -2 knockout mice demonstrate increased cardiac ischemia/reperfusion injury but are protected by acute preconditioning. Circulation 2001;104(20):2453-8.
Kwak HJ, Park KM, Choi HE, et al. The cardioprotective effects of zileuton, a 5-lipoxygenase inhibitor, are mediated by COX-2 via activation of PKC delta. Cell Signal 2010;22(1):80-7.
Berti F, Rossoni G, Magni F, et al. Nonsteroidal antiinflammatory drugs aggravate acute myocardial ischemia in the perfused rabbit heart: a role for prostacyclin. J Cardiovasc Pharmacol 1988;12(4):438-44.
Rossoni G, Berti M, Colonna VD, et al. Myocardial protection by the nitroderivative of aspirin, NCX 4016: in vitro and in vivo experiments in the rabbit. Ital Heart J 2000;1(2):146-55.
Penna C, Mancardi D, Tullio F, et al. Postconditioning and,intermittent bradykinin induced cardioprotection require cyclooxygenase activation and prostacyclin release during reperfusion. Basic Res Cardiol 2008;103(4):368-77.
McGuinness J, Neilan TG, Cummins R, et al. Intravenous glutamine enhances COX-2 activity giving cardioprotection. J Surg Res 2009;152(1):140-7.
Homeida AM, Al-Eknah MM. Inhibition of luteal function by oxytocin antagonist in goats (Capra hircus). J Reprod Fertil 1992;94(1):279-85.
Penrod LV, Allen RE, Turner JL, et al. Effects of oxytocin, lipopolysaccharide (LPS), and polyunsaturated fatty acids on prostaglandin secretion and gene expression in equine endometrial explant cultures. Domest Anim Endocrinol 2013; 44(1):46-55.
Gutkowska J, Jankowski M, Mukaddam-Daher S, et al. Oxytocin is a cardiovascular hormone. Braz J Med Biol Res 2000;33(6):625-33.
Jankowski M, Wang D, Hajjar F, et al. Oxytocin and its receptors are synthesized in the rat vasculature. Proc Natl Acad Sci U S A 2000;97(11):6207-11.
Tshivhula F, Grove D, Odendaal HJ. The effects of atosiban on abnormal fetal heart rate patterns. Eur J Obstet Gynecol Reprod Biol 2007;133(2):248-9.
Alizadeh AM, Faghihi M, Sadeghipour HR, et al. Role of endogenous oxytocin in cardiac ischemic preconditioning. Regul Pept 2011;167(1):86-90.
Anvari MA, Imani A, Faghihi M, et al. The administration of oxytocin during early reperfusion, dose-dependently protects the isolated male rat heart against ischemia/reperfusion injury. Eur J Pharmacol 2012; 682(1-3):137-41.
Gutkowska J, Jankowski M. Oxytocin revisited: its role in cardiovascular regulation. J Neuroendocrinol 2012;24(4):599-608.
Clark SL, Simpson KR, Knox GE, et al. Oxytocin: new perspectives on an old drug. Am J Obstet Gynecol 2009;200(1):35 e31-6.
Jaburek M, Costa AD, Burton JR, et al. Mitochondrial PKC epsilon and mitochondrial ATP-sensitive K+ channel copurify and coreconstitute to form a functioning signaling module in proteoliposomes. Circ Res 2006;99(8):878-83.
Schuh J, Fairclough GF, Jr., Haschemeyer RH. Oxygenmediated heterogeneity of apo-low-density lipoprotein. Proc Natl Acad Sci U S A 1978;75(7):3173-7.
Guo JY, Yang T, Sun XG, et al. Ischemic postconditioning attenuates liver warm ischemia-reperfusion injury through Akt-eNOS-NO-HIF pathway. J Biomed Scie 2011;18(1):79.
Jones SP, Greer JJ, Kakkar AK, et al. Endothelial nitric oxide synthase overexpression attenuates myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 2004;286(1):H276-82.
Biyikli NK, Tugtepe H, Sener G, et al. Oxytocin alleviates oxidative renal injury in pyelonephritic rats via a neutrophil-dependent mechanism. Peptides 2006;27(9):2249-57.
37. Ronson RS, Nakamura M, Vinten-Johansen J. The cardiovascular effects and implications of peroxynitrite. Cardiovasc Res 1999;44(1):47-59.
38. Cai M, Li YJ, Xu Y, et al. Endothelial NOS activity and myocardial oxygen metabolism define the salvageable ischemic time window for ischemic postconditioning. Am J Physiol Heart Circ Physiol 2011;300(3):H1069-77.
Burley DS, Baxter GF. B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart. Basic Res Cardiol 2007;102(6):529-41.
Liu X, Chen H, Zhan B, et al. Attenuation of reperfusion injury by renal ischemic postconditioning: the role of NO. Biochem Biophys Res Commun 2007;359(3):628-34.
Krolikowski JG, Weihrauch D, Bienengraeber M, et al. Role of Erk1/2, p70s6K, and eNOS in isoflurane-induced cardioprotection during early reperfusion in vivo. Can J Anaesth 2006;53(2):174-82.
Tugtepe H, Sener G, Biyikli NK, et al. The protective effect of oxytocin on renal ischemia/reperfusion injury in rats. Regul Pept 2007;140(3):101-8.
Wilde AA, Janse MJ. Electrophysiological effects of ATP sensitive potassium channel modulation: implications for arrhythmogenesis. Cardiovasc Res 1994;28(1):16-24.
Riess ML, Camara AK, Heinen A, et al. KATP channel openers have opposite effects on mitochondrial respiration under different energetic conditions. J Cardiovasc Pharmacol 2008;51(5):483-91.
Costa AD, Garlid KD, West IC, et al. Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res 2005;97(4):329-36.
Costa AD, Jakob R, Costa CL, et al. The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition. J Biol Chem 2006;281(30):20801-8.
Huh J, Gross GJ, Nagase H, et al. Protection of cardiac myocytes via delta(1)-opioid receptors, protein kinase C, and mitochondrial K(ATP) channels. Am J Physiol Heart Circ Physiol 2001;280(1):H377-83.
Liu H, McPherson BC, Zhu X, et al. Role of nitric oxide and protein kinase C in ACh-induced cardioprotection. Am J Physiol Heart Circ Physiol 2001;281(1):H191-7.
Yoshida H, Kusama Y, Kodani E, et al. Pharmacological preconditioning with bradykinin affords myocardial protection through NO-dependent mechanisms. Int Heart J 2005;46(5):877-87.
Lebuffe G, Schumacker PT, Shao ZH, et al. ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel. Am J Physiol Heart Circ Physiol 2003;284(1):H299-308.
Sasaki N, Sato T, Ohler A, et al. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation 2000;101(4):439-45.
Mollace V, Muscoli C, Masini E, et al. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev 2005;57(2):217-52.
Franco L, Doria D. Nitric oxide enhances prostaglandin production in ethanol-induced gastric mucosal injury in= rats. Eur J Pharmacol 1998;348(2-3):247-56.
Bouchard JF, Chouinard J, Lamontagne D. Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart. Cardiovasc Res 2000;45(2):418-27.
Liu X, Zhou Z, Feng X, et al. Cyclooxygenase-2 plays an essential part in cardioprotection of delayed phase of recombinant human erythropoietin preconditioning in rats. Postgrad Med J 2006;82(971):588-93.
Hide EJ, Ney P, Piper J, et al. Reduction by prostaglandin E1 or prostaglandin E0 of myocardial infarct size in the rabbit by activation of ATP-sensitive potassium channels. Br J Pharmacol 1995;116(5):2435-40.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.